Generating irreversible electroporation and radiofrequency-abaltion (ire/rfa) waveforms

ABSTRACT

An irreversible electroporation and radio frequency ablation (IRE/RFA) generator includes an IRE pulse generator, harmonic filtration circuitry, and a waveform interleaver. The IRE pulse generator is configured to generate biphasic IRE pulses. The harmonic filtration circuitry is configured to convert the IRE pulses into an RF signal. The waveform interleaver, which is configured to receive the IRE pulses and the RF signal and generate an output signal having a composition of the adapted IRE pulses having a final shape and repetition rate, the converted RF sinusoidal signal, or a combined IRE/RFA output signal, by switching between the received IRE square pulses and the received converted RF sinusoidal signal.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation application of U.S. application Ser.No. 16/704,421, filed Dec. 5, 2019, which is incorporated herein byreference.

FIELD OF THE INVENTION

The present invention relates generally to methods and systems forcombined irreversible electroporation and radiofrequency ablationtreatments, and particularly to combined irreversible electroporationand radiofrequency ablation waveform generation.

BACKGROUND OF THE INVENTION

Delivery of radiofrequency (RF) pulses to tissue was previously proposedin the patent literature. For example, U.S. Pat. No. 10,258,406describes a computer-implemented system for delivering energy to tissuehaving a necrotic threshold. The system may generally include anelectrode array comprising a plurality of electrodes, a centralelectrode positioned intermediate the plurality of electrodes, and acontroller configured to (i) apply a first sequence of electrical pulsesto the electrode array to induce thermal heating in the tissue andreduce the necrotic threshold of the tissue, and (ii) apply a secondsequence of electrical pulses to the central electrode to induce cellnecrosis in the tissue by irreversible electroporation. In an exemplaryembodiment, an energy source may be configured to generate electricpulses at frequencies in the range of about 1 Hz to about 10,000 Hz,amplitudes in the range of about +/−100 VDC to about +/−6,000 VDC, andpulse width in the range of about 1 μSec to about 100 mSec. The energysource may be configured to generate the electric pulses suitable toinduce thermal heating and pulses suitable to irreversibleelectroporation in the tissue. The energy source may be operated inbiphasic mode and monophasic mode.

As another example, U.S. Pat. No. 10,188,449 describes anelectrosurgical generator that includes: a power supply configured tooutput DC power, an inverter coupled to the power supply, the inverterincluding a plurality of switching elements, and a controller coupled tothe inverter and configured to signal the inverter to simultaneouslygenerate based on the DC power a radio frequency heating waveform and anelectroporation waveform. In an exemplary embodiment, a controllercoupled to inverter circuitry is configured to signal the invertercircuitry to simultaneously generate, based on the DC power, a radiofrequency heating waveform and an electroporation waveform, which is apulsatile DC waveform configured to generate an electric field andincludes a plurality of pulses having an initial pulse with a higherpeak voltage and a higher rate of increase of voltage than anysubsequent pulse.

U.S. Pat. No. 9,289,606 describes catheter systems that includedirection-sensitive, multi-polar tip electrode assemblies forelectroporation-mediated therapy, electroporation-induced primarynecrosis therapy and electric field-induced apoptosis therapy, includingconfigurations for producing narrow, linear lesions as well asdistributed, wide area lesions. For electroporation-induced primarynecrosis therapy, a generator may be configured to produce an electriccurrent that is delivered via the electrode assembly as a pulsedelectric field in the form of short-duration pulses (e.g., 0.1 to 20mSec duration) between closely spaced electrodes capable of delivering arelatively low electric field strength (i.e., at the tissue site) ofabout 0.1 to 1.0 kV/cm. For electric field-induced apoptosis therapy,the generator may be configured to produce an electric current that isdelivered as a pulsed electric field in the form of extremelyshort-duration direct current pulses (e.g., 1 to 300 nSec duration) at arelatively high electric field strength (i.e., at the tissue site) ofabout 2 to 300 kV/cm. In certain other exemplary embodiments, such aselectroporation-mediated ablation therapy, both electroporation specificenergy as well as ablation specific energy will be used in the overallprocess and in such embodiments, the generator may be further configuredto deliver ablation energy as well.

SUMMARY OF THE INVENTION

An exemplary embodiment of the present invention provides anirreversible electroporation and radio frequency ablation (IRE/RFA)generator including an IRE pulse generator, harmonic filtrationcircuitry, and a waveform interleaver. The IRE pulse generator isconfigured to generate biphasic IRE pulses. The harmonic filtrationcircuitry is configured to convert the IRE pulses into an RF signal. Thewaveform interleaver, which is configured to receive the IRE pulses andthe RF signal and generate an IRE/RFA output signal by interleaving inalternation one or more of the IRE pulses with one or more periods ofthe RF signal.

In some exemplary embodiments, the waveform interleaver is configured toreceive, from a processor, a setting that specifies an interleavingratio between the IRE pulses and the periods of the RF signal, and togenerate the interleaved IRE/RFA output signal responsively to thesetting.

In some exemplary embodiments, the IRE pulse generator is configured toreceive, from a processor, a setting that specifies one or more of ashape, an amplitude and a repetition rate of the IRE pulses, and togenerate the biphasic IRE pulses responsively to the setting.

In an exemplary embodiment, the harmonic filtration circuitry isconfigured to receive, from a processor, a setting that specifies one ormore of a frequency and amplitude of the RF signal, and to convert theIRE pulses into the RF signal responsively to the setting.

In an exemplary embodiment, the IRE/RFA generator further includes IREpulse shaping circuitry, configured to apply a prespecified pulse-shapeto the IRE pulses.

In some exemplary embodiments, the waveform interleaver is configured tointerleave the IRE pulses with the RF signal in accordance with aconfigurable treatment protocol.

There is additionally provided, in accordance with another exemplaryembodiment of the present invention, a method of generation ofirreversible electroporation and radio frequency ablation (IRE/RFA)signals, the method including generating biphasic IRE pulses. Usingharmonic filtration circuitry, the IRE pulses are converted into an RFsignal. an IRE/RFA output signal is generated by interleaving one ormore of the IRE pulses with one or more periods of the RF signal.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will be more fully understood from the followingdetailed description of the embodiments thereof, taken together with thedrawings in which:

FIG. 1 is a schematic, pictorial illustration of a catheter-basedIRE/RFA system, in accordance with an exemplary embodiment of thepresent invention;

FIG. 2 is a schematic block diagram of the IRE/RFA generator of thesystem of FIG. 1 , in accordance with an exemplary embodiment of thepresent invention;

FIG. 3 is a schematic block diagram showing certain details of theIRE/RFA generator of FIG. 2 , in accordance with an exemplary embodimentof the present invention; and

FIG. 4 is a flow chart that schematically illustrates a method forIRE/RFA treatment using the IRE/RFA system of FIG. 1 , in accordancewith an exemplary embodiment of the present invention.

DETAILED DESCRIPTION OF EMBODIMENTS

Overview

Radiofrequency ablation (RFA) and irreversible electroporation (IRE),which are used as invasive therapeutic modalities, may havecomplimentary clinical attributes. RFA destroys tissue cells with heatby dissipating electrical energy in tissue, whereas IRE destroys tissuecells by subjecting tissue to strong electric field pulses, with minimaldissipation of electrical energy in tissue.

It is anticipated that, by combining IRE and RFA, a more effectivetreatment may be achieved. For example, thermally assisted IRE may leadto a more complete ablation, in which tissue insufficiently destroyed byone modality, due to, for example, tissue geometry and/or composition,will be subsequently fully destroyed by the other modality. However,delivering the aforementioned treatments, one after the other, may notbe as effective in some applications, such as cardiac treatments, dueto, for example, cardiac motion.

Exemplary embodiments of the present invention that are describedhereinafter provide systems and methods for joint delivery of IRE andRFA treatments to the same location. In the disclosed technique, alsonamed hereinafter “IRE/RFA,” sequences of IRE and RFA waveforms that areintertwined, interweaved and/or interleaved on a sub-second scale aregenerated and delivered. In an exemplary embodiment, IRE pulses and RFAcycles are applied to the same tissue location at the same time byinterleaving one or more IRE pulses with one or more RFA cycles on thesame ablation electrode, according to a preset interleaving ratio.

In some exemplary embodiments, a generator is provided that can vary itsoutput sequence of waveforms to apply only IRE pulses, only RF cycles,or sequences of M IRE pulses and N RFA cycles in alternation, with M≥1,N≥1.

Other properties of the sequence may be configured through a processorthat controls the generator, for example, IRE pulse shape and amplitude,and pulse repetition rate, as well RFA parameters, such as RF frequency.Typically, for IRE, the generator is able to generate biphasic pulseswith peak to peak voltages of up to 4 kV, and at typical pulse widths ofμSec. For RFA, the generator is able to generate sinusoidal cycles withpeak to peak voltages of up to 100V with mSec periodicity.

In some exemplary embodiments, an operator of the disclosed generator,e.g., using a user interface in a processor, may select, for example, anenergy scale, such as 100 percent IRE (represented by N=0), 100 percentRFA (represented by M=0), or any ratio in between. The generator isprogrammed to provide, for example using a configurable protocol, thecorrect sequence of {M, N} interleaved waveforms according to theoperator selection. Such a configurable protocol may further include,for example, pulse width and pulse amplitude that yield the requiredselection.

In some exemplary embodiments, the disclosed generator produces an RFsignal (e.g., cycles) from IRE pulses using (a) harmonic filtrationcircuitry, and (b) IRE/RFA switching circuitry, both included in thedisclosed generator. To generate waveforms for RFA, the disclosedharmonic filtration may apply, to an IRE waveform, one or more of thefollowing according to a given embodiment: low-pass filtration,band-pass filtration, or band-stop filtration.

The disclosed IRE/RPA generator enables the application of IRE and RFAtreatments to the same location at the same time, and thus may improvethe clinical outcome of invasive treatments of cardiac arrhythmia.

System Description

FIG. 1 is a schematic, pictorial illustration of a catheter-basedIRE/RFA system 20, in accordance with an exemplary embodiment of thepresent invention. System 20 comprises a catheter 21, wherein a shaft 22of the catheter is inserted into a heart 26 of a patient 28 through asheath 23. The proximal end of catheter 21 is connected to a console 24.

Console 24 comprises an IRE/RFA generator 38 for applying intertwinedIRE/RFA waveforms via catheter 21 to ablate tissue in a left atrium 45of heart 26. In the exemplary embodiment described herein, catheter 21may be used for any suitable therapeutic and/or diagnostic purpose, suchas electrical sensing and/or isolation of ostium tissue of a pulmonaryvein in left atrium 45 of heart 26.

A physician 30 inserts shaft 22 through the vascular system of patient28. As seen in inset 25, an inflatable balloon 40 is fitted at thedistal end of shaft 22. During the insertion of shaft 22, balloon 40 ismaintained in a collapsed configuration inside sheath 23. By containingballoon 40 in a collapsed configuration, sheath 23 also serves tominimize vascular trauma along the way to the target location. Physician30 navigates the distal end of shaft 22 to a target location in heart26.

Once the distal end of shaft 22 has reached the target location,physician 30 retracts sheath 23 to expand balloon 40. Physician 30 thenmanipulates shaft 22 such that electrodes disposed on balloon 40 engagean interior wall of the ostium.

Console 24 comprises a processor 41, typically a general-purposecomputer, with suitable front end and interface circuits 37 forreceiving signals from catheter 21 and from external-electrodes 49,which are typically placed around the chest of patient 26. For thispurpose, processor 41 is connected to external electrodes 49 by wiresrunning through a cable 39. In an exemplary embodiment, physician 30diagnoses an arrhythmogenic tissue location, using, for example,electrophysiological signals acquired by catheter 21. Subsequently,physician 30 applies, via the electrodes disposed on balloon 40, anintertwined IRE/RFA waveform to ablate tissue.

Processor 41 is typically programmed (software) to carry out thefunctions described herein. The software may be downloaded to thecomputer in electronic form, over a network, for example, or it may,alternatively or additionally, be provided and/or stored onnon-transitory tangible media, such as magnetic, optical, or electronicmemory.

Although the illustrated exemplary embodiment relates specifically tothe use of a balloon for ablation of heart tissue, the elements ofsystem 20 and the methods described herein may alternatively be appliedin controlling ablation using other sorts of multi-electrode ablationdevices, such as multi-arm ablation catheters. In other words, anysuitable device may be utilized in accordance with the presentinvention.

Generation of Sequence of Interleaved IRE/RFA Waveforms

FIG. 2 is a schematic block diagram of IRE/RFA generator 38 of thesystem 20 illustrated in FIG. 1 , in accordance with an exemplaryembodiment of the present invention. In the illustrated exemplaryembodiment, generator 38 comprises an IRE pulse generator 50 and anIRE/RFA waveform shaper and interleaver 55, which are both configurableand controlled by processor 41.

As illustrated, IRE pulse generator 50 generates a sequence 52 ofhigh-voltage IRE biphasic pulses of a predefined waveform. In thepresent context, the term “biphasic pulse” refers to a pulse having apositive-voltage phase and a negative-voltage phase, such that theaverage voltage of the pulse is zero volts. In an exemplary embodiment,but not necessarily, the biphasic pulses have a square-wave pulse-shape.In some exemplary embodiments, the peak-to-peak voltage of the biphasicpulse is on the order of up to 4 KV, i.e., ±2 KV. The pulse width ofeach biphasic pulse is typically on the order of several microseconds.Alternatively, any other suitable pulse parameters may be used.

IRE/RFA waveform shaper and interleaver 55, further described in FIG. 3, converts input sequence 52 into an interleaved IRE/RFA sequence 57 ofoutput waveforms comprising, by way of example, M=2 IRE shape pulsesinterleaved with N=2 sinusoidal periods (e.g., two sinus shaped pulses)of RF energy. IRE/RFA sequence 57 is typically delivered to catheter 22,for application to a selected tissue location via an ablation electrodeas described above with reference to FIG. 1 .

FIG. 3 is a schematic block diagram showing certain details of IRE/RFAgenerator 38 of FIG. 2 , in accordance with an exemplary embodiment ofthe present invention. In the present example, IRE/RFA waveform shaperand pulse interleaver 55 comprises biphasic pulse shaper circuitry 60,harmonic filter circuitry 64, and waveform interleaver circuitry 66.

Biphasic pulse shaper circuitry 60 is configured to adapt IRE pulses ofsequence 52, if required, to IRE pulses 62 having a final shape andrepetition rate. For example, pulse shaper 60 may comprise an array ofcapacitors for producing different rise times and/or fall times of thebiphasic pulses.

Harmonic filter circuitry 64 may comprise a set of harmonic filters ofsome of the types described above, and may be configured, based onsettings provided by processor 41, to convert the input IRE pulses ofsequence 52 into an RF signal 59, typically a sinusoidal signal. RFsignal 59 typically has a frequency on the order of 450 kHz-500 kHz andpeak-to-peak voltage on the order of up to 100V (i.e., ±50V).Alternatively, however, any other suitable signal parameters may beused.

As seen in an inset 65, harmonic filtration may be performed by a lowpass filter (represented by a capacitor), while output voltage isdetermined using one or more transformers. Finally, waveform interleaver66 interleaves one or more IRE pulses 62 with one or more periods of RFsignal 59 and outputs the interleaved sequence 57 to catheter 21. Asseen, waveform interleaver 66 comprises a switching circuitry 67 toswitch between input waveforms 59 and 62.

Harmonic filtration is one of the simplest ways in which to convert asquare wave into a sine wave. A square wave consists of a fundamentalfrequency and higher order harmonics. The harmonic filtration serves toremove the higher order harmonics thereby leaving the sinusoidalfundamental frequency signal.

The exemplary configurations shown in FIGS. 2 and 3 are chosen purelyfor the sake of conceptual clarity. In alternative exemplaryembodiments, the disclosed techniques may use any other suitable pulsegeneration and shaping schemes.

FIG. 4 is a flow chart that schematically illustrates a method forIRE/RFA treatment using IRE/RFA system 20 of FIG. 1 , in accordance withan exemplary embodiment of the present invention. The process beginswith physician 30 inserting catheter 20 into heart 26, at a catheterinsertion step 70. Next, physician 30 selects a ratio of IRE/RFA energyto be delivered to the target tissue, for example, by selecting apredefined protocol, at a therapeutic energy selection step, 72. Asnoted above, physician 30 may select any ratio between 100 percent IREenergy to 100 percent RFA energy, depending on the clinical target.

Assuming physician 30 chooses to apply a mixture of IRE and RFA energy,physician 30 specifies an interleaved sequence of IRE/RFA waveforms, forexample, as specified by the selected protocol, at an interleavedsequence selection step, 74. For example, physician 30 may select an{M=1, N=1} sequence, as defined above, which has a maximal degree ofinterleaving.

Next, at catheter positioning step 76, physician 30 manipulates catheter21 to establish contact between electrodes disposed on balloon 40 andtissue, such as of an ostium of a pulmonary vein. Next, physician 30applies the selected interleaved sequence of IRE/RFA waveforms totissue, at an IRE/RFA treatment step 78.

Immediately after treatment, at a post IRE/RFA treatment diagnostic step80, physician 30 uses balloon 40 as a diagnostic catheter to acquireelectrograms to check to what extent treatment step 78 achievedisolation. If, at a checking step 82, the physician finds thatsufficient isolation was achieved, physician 30 then removes thecatheter from the patient body, at a catheter retraction step 84.Otherwise, physician 30 may reposition the balloon for additionaltreatment by looping back to step 72 to select parameters of theadditional treatment step.

Although the embodiments described herein mainly address cardiacapplications, the methods and systems described herein can also be usedin other medical applications, such as in treatment of solid tumors,such as in lungs or liver.

It will thus be appreciated that the exemplary embodiments describedabove are cited by way of example, and that the present invention is notlimited to what has been particularly shown and described hereinabove.Rather, the scope of the present invention includes both combinationsand sub-combinations of the various features described hereinabove, aswell as variations and modifications thereof which would occur topersons skilled in the art upon reading the foregoing description andwhich are not disclosed in the prior art. Documents incorporated byreference in the present patent application are to be considered anintegral part of the application except that to the extent any terms aredefined in these incorporated documents in a manner that conflicts withthe definitions made explicitly or implicitly in the presentspecification, only the definitions in the present specification shouldbe considered.

1. A system for combining irreversible electroporation and radiofrequency ablation (IRE/RFA), comprising: an IRE pulse generatorconfigured to generate biphasic IRE square pulses; a biphasic pulseshaper, configured and controlled by a processor, to adapt the biphasicIRE square pulses to IRE pulses having a final shape and repetitionrate; one or more harmonic filters, configured and controlled by theprocessor, to convert the biphasic IRE square pulses into an RFsinusoidal signal; and a waveform interleaver comprising switchingcircuitry, which is configured and controlled by the processor, toreceive the IRE square pulses and the converted RF sinusoidal signal andgenerate an output signal having a composition comprising one of: i) theadapted IRE pulses having a final shape and repetition rate, ii) theconverted RF sinusoidal signal, or iii) a combined IRE/RFA output signalby switching between the received IRE square pulses and the receivedconverted RF sinusoidal signal.
 2. The system of claim 1, wherein thecombined IRE/RFA output signal comprises one or more of the IRE squarepulses with one or more periods of the converted RF sinusoidal signalinterleaved in alternation into a single waveform.
 3. The system ofclaim 1, wherein the composition of the generated output signal isone-hundred percent (100%) IRE square pulses.
 4. The system of claim 1,wherein the composition of the generated output signal is one-hundredpercent (100%) converted RF sinusoidal signal.
 5. The system of claim 1,wherein the composition of the generated output signal is a ratiobetween one-hundred percent (100%) IRE square pulses and one-hundredpercent (100%) converted RF sinusoidal signal.
 6. A method for combiningirreversible electroporation and radio frequency ablation (IRE/RFA),comprising: generating biphasic IRE square pulses; adapting the biphasicIRE square pulses to IRE pulses having a final shape and repetitionrate; using one or more harmonic filters, configured by a processor,converting the IRE square pulses into an RF sinusoidal signal; andreceiving the IRE square pulses and the converted RF sinusoidal signaland generating, by a waveform interleaver comprising switching circuitrycontrolled by the processor, in response to receiving an input via auser interface, an output signal having a composition comprising one of:i) the adapted IRE pulses having a final shape and repetition rate, ii)the converted RF sinusoidal signal, or iii) a combined IRE/RFA outputsignal by switching between the received IRE square pulses and thereceived converted RF sinusoidal signal.
 7. The method of claim 6,wherein the combined IRE/RFA output signal comprises one or more of theIRE square pulses with one or more periods of the converted RFsinusoidal signal interleaved in alternation into a single waveform. 8.The method of claim 6, wherein the composition of the generated outputsignal is one-hundred percent (100%) IRE square pulses.
 9. The method ofclaim 6, wherein the composition of the generated output signal isone-hundred percent (100%) converted RF sinusoidal signal.
 10. Themethod of claim 6, wherein the composition of the generated outputsignal is a ratio between one-hundred percent (100%) IRE square pulsesand one-hundred percent (100%) converted RF sinusoidal signal.
 11. Acomputer program product, comprising a non-transitory computer-readablemedium having computer-readable program code embodied therein to beexecuted by one or more processors, the program code includinginstructions to: cause biphasic IRE square pulses to be generated; causethe biphasic IRE square pulses to be adapted to IRE pulses having afinal shape and repetition rate; cause, using one or more harmonicfilters, the IRE square pulses to be converted into an RF sinusoidalsignal; and receive the IRE square pulses and the converted RFsinusoidal signal and generate, by a waveform interleaver comprisingswitching circuitry controlled by the processor, in response toreceiving an input via a user interface, an output signal having acomposition comprising one of: i) the adapted IRE pulses having a finalshape and repetition rate, ii) the converted RF sinusoidal signal, oriii) a combined IRE/RFA output signal by switching between the receivedIRE square pulses and the received converted RF sinusoidal signal. 12.The computer program product of claim 11, wherein the combined IRE/RFAoutput signal comprises one or more of the IRE square pulses with one ormore periods of the converted RF sinusoidal signal interleaved inalternation into a single waveform.
 13. The computer program product ofclaim 9, wherein the composition of the generated output signal isone-hundred percent (100%) IRE square pulses.
 14. The computer programproduct of claim 9, wherein the composition of the generated outputsignal is one-hundred percent (100%) converted RF sinusoidal signal. 15.The computer program product of claim 9, wherein the composition of thegenerated output signal is a ratio between one-hundred percent (100%)IRE square pulses and one-hundred percent (100%) converted RF sinusoidalsignal.